Deregulated Wnt signaling has been observed in a number of human cancers. Even though increased levels of nuclear beta-catenin have been observed in aggressive forms of human prostate cancer and are very good evidence of an activated canonical Wnt signaling pathway, no direct or causal relationship between deregulation of the Wnt signaling axis and initiation, progression, metastasis or development of androgen depletion independent (ADI) disease has been demonstrated. The research outlined in this proposal will test the central hypothesis that deregulated Wnt signaling can indeed cause prostate cancer through three interrelated specific aims: 1) determine the consequence of enforced expression of the proto-oncogene, Wnt3, on epithelial cells of the mouse prostate, 2) determine the consequence of enforced Wnt3 expression during tumor progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model and 3) determine the influence of Wnt signaling on tumor growth and differentiation in an allograft model using prostate cancer derived cell lines engineered to express high levels Wnt3. The long-term objectives of this research will increase our understanding of how Wnt signaling contributes to prostate cancer, examine the role that deregulated Wnt signaling plays in deadly bone metastases and facilitate development of new treatment strategies. Relevance to Public Health: The research outlined in this proposal has direct relevance to a major public health concern, prostate cancer. The work will exploit genetically engineered mouse models to expand current understanding of the role that activation of the Wnt/beta-catenin pathway plays in prostate biology and cancer.